Thrombosis, the formation and development of a blood clot or thrombus within the vascular system, while a life saving process when it occurs during a hemorrhage, can be life threatening when it occurs at any other time. The thrombus can block a vessel and stop blood supply to an organ or other body part. If detached, the thrombus can become an embolus and occlude a vessel distant from the original site.
In the healthy person there is a balance between clot formation (thrombosis) which is needed to minimize blood loss and to repair blood vessels, and clot lysis (fibronolysis) which maintains the patency of blood vessels. When thrombosis occurs without concomitant fibronolysis effects can lead to strokes.
Traditional thrombolytic agents used are not clot specific and while they do break up the thrombus and facilitate fibronolysis they also put the patient at significant risk as all clotting is inhibited and a patient could bleed to death from a small abrasion elsewhere. Current thrombolytic agents include streptokinase which is derived from Beta-hemolytic streptococci. When combined with plasminogen, streptokinase catalyzes the conversion of plasminogen to plasmin, the enzyme responsible for clot dissolution in the body. Three major problems encountered with the use of streptokinase therapy include its systemic lytic effects coupled with a long half life. Because the anticoagulant activity of streptokinase is indiscriminent (non clot specific) and prolonged (half life 10-18 minutes), bleeding is a common complication which must be carefully monitored during 12 hours following immediately after administration. Further because streptokinase is a bacterial protein, it is strongly antigenic and can produce a variety of allergic reactions including anaphylaxis, particularly when administered to a patient who has previously received streptokinase therapy or who has had a recent streptococcal infection.
Another popular agent for use in treatment of thrombosis is urokinase, an enzyme protein secreted by the parenchyma cells of the human kidney. It acts to direct activation of plasminogen to form plasmin. This is different from streptokinase which first forms a complex with plasminogen to activate plasmin to dissolve the clot. Urokinase is also non clot specific (activates circulating non clot bound plasminogen as well as clot bound plasminogen) but has a shorter half life than streptokinase. Its administration is associated with fewer bleeding complications despite the fact that a systemic lytic state is also produced. Urokinase is produced by the kidney and as such it is not antigenic and well suited for use if subsequent thrombolytic therapy is needed. The major problem with urokinase is that it is difficult and expensive to produce precluding its extensive clinical use.
The most recently developed drug in treating of thrombolysis is recombinant tissue plasminogen activator. Approved by the FDA in November of 1987, tissue plasminogen activator (t-PA) is a naturally occurring enzyme (thus non antigenic) that is clot specific and has a very short half life (3-5 minutes). It converts plasminogen to plasmin after binding to the fibrin-containing clot. This clot specificity results in an increased concentration and activity of plasmin at the site of the clot, where it is needed. This characteristic of t-PA prevents the induction of the systemic lytic state that occurs with streptokinase and urokinase activity. However the results of studies comparing the streptokinase and t-PA show similar incidences of bleeding following administration. Successful gene cloning has made sufficient quantities of t-PA available for clinical use, however, the recombinant technology necessary for its production have also resulted in a prohibitive cost. As can be seen a need in the art exists for a thrombolysis therapy which is clot specific, which does not induce a systemic lytic state and which is inexpensive and non antigenic to patients.